Large-scale genetics studies on schizophrenia to date have failed to discover a substantial contribution of common genetic variation. However, recent analyses of structural genetic variation have identified and rapidly confirmed a number of rare variants contributing to this disorder. Surprisingly, the same rare genetic contributors have often been found to be risk factors for multiple neuropsychiatric conditions, including schizophrenia, mental retardation, autism and epilepsy. This suggests that these rare variants may confer a "neuropsychiatric vulnerability" and that the ultimate manifestation depends on other genetic or environmental influences. This suggests that patients with multiple co-occurring conditions may be those most likely to carry an elevated burden of rare, high-penetrant risk factors. Additionally, families that have multiple neuropsychiatric conditions associated with the same rare genetic variant could be the most valuable in dissecting the genetic and environmental influences on mental disorders. With this research, we propose to collect 100 chronically mentally ill patients with schizophrenia or schizoaffective disorder and as many of their first, second and third degree relatives as possible, and to perform whole-genome sequencing to identify rare gene variants that predispose to disease with relatively high-penetrance. Using DNA collected from these subjects, we will use next-generation whole genome sequencing technology and a variety of novel bioinformatic tools to select potentially disease-associated gene variants on the basis of predicted function and frequency in healthy control populations. We will then examine the distribution of associated variants in the families, determining which disorders, symptoms or traits they are associated with, and what differences in environment and genetic background are present between affected and unaffected carriers. By focusing on patients with a strong genetic burden and a family history of mental illness, and including the entire genome in our search for genetic susceptibility, we expect to be able to find rare highly penetrant variants that would be undetectable with other approaches. PUBLIC HEALTH RELEVANCE: Schizophrenia is a highly heritable neuropsychiatric condition that affects millions of individuals in the U.S. alone. The proposed study seeks to increase our understanding of the genetic basis of this disease by performing whole-genome sequencing in 100 schizophrenia patients to search for rare, highly penetrant associated genetic variants. Potentially associated genetic markers will be genotyped in affected and unaffected family members to determine their specificity for schizophrenia, and to investigate genetic and environmental modifiers of their effects. This work could elucidate the molecular basis of schizophrenia and potentially indicate novel targets for psychiatric drugs.